Emerging technologies for manufacture and use of nanoparticles (NP) are numerous and the exponential increase in their use drives the need for understanding toxicology of these particles. Most non-carbon NP contain one or more toxicologically-active metals, including cadmium (Cd). As NP-induced reprotoxicity has yet to be addressed in animal studies and because bulk Cd: is an endocrine disruptor;reduces progesterone levels;alters placental steroidogenesis;can concentrate in the placenta;and, exposure to bulk Cd is associated with fetal instability (i.e., low birth weight [LBW], and pre-term delivery [PTD]), a study is proposed to determine how inhalation of Cd-bearing NP (as CdO and CdTe) might impair fetal stability in utero, and how these effects are related to physicochemical properties of the particles. We hypothesize that: (1) exposure of pregnant mice to atmospheres containing Cd-bearing (Cd) NP will display reductions in gestational duration/birth weight/fetal growth that are related to particle physicochemical properties and, (2) these outcomes are a result of property-dependent effects on the release and actions of select hormones/cytokines important for pregnancy maintenance and parturition. Timed-pregnant mice exposed to relevant levels of either nanosize (i.e., fresh) or agglomerated (i.e., aged) CdO or CdTe (or size-matched carbon particles) will be sacrificed on gestational day (GD) 18 or allowed to give birth. Biologic samples collected from each dam will be used in four inter-related Aims to examine effects of inhaled manufactured Cd NP on: 1) PTD/LBW/restricted fetal growth as a function of physicochemical properties of the inhaled particles;2) GD18 hormone levels critical for pregnancy maintenance/preparation of parturition;3) changes in hormone responsiveness (by examining receptor/hormone expression) shown to be altered in Aim 2);and 4) uterine sensitivity to oxytocin- induced contractions, and cervical dilatability using an ex vivo organ bath system established from mice sacrificed on GD18. Because: reduction in size can potentiate particle toxicity;Cd from inhaled nanosize CdO can reach the placenta of exposed mouse dams (c.f., Preliminary studies);large numbers of pregnant women will potentially be exposed to Cd-associated nanomaterials;bulk Cd, a potent estrogen mimic, concentrates in the placenta and produces placental toxicity leading to LBW and PTD;pregnant women/fetuses are particularly vulnerable to toxic insult;and, there is a disquieting absence of reproductive toxicology studies examining NP, an investigation is proposed whose major goal is to link physiochemical parameters of Cd-bearing NP with potential adverse reproductive outcomes. Results will provide initial hazard characterization of Cd NP (with regards to their potential for reproductive effects that will be useful in setting appropriate standards/guidelines for pregnant women/fetuses. The proposed studies fit well into the NIEHS program that highlights the need for studies of nanoscale materials that explore the development of appropriate novel toxicological methods to assess potential human health effects. PUBLIC HEALTH RELEVANCE: The proposed studies are designed to determine the reproductive toxicity of cadmium nanoparticles on pregnancy stability and parturition in a mouse model. The approach is designed to identify such effects as preterm birth induction, low birth weight and/or restricted fetal growth and underlying hormonal/cytokine dysregulation in relation to the physicochemical properties of the cadmium nanoparticles. The findings will have great relevance to the health of women of reproductive age, particularly in the workplace, in harmony with the NIEHS and National Toxicology Program (NTP) broad-based research program to address potential human health hazards associated with the manufacture and use of nanoscale materials.